The elucidation of the molecular defects in patients with high cholesterol and triglycerides provides the unique opportunity to develop more effective approaches to screen individuals with an increased risk of premature heart disease and to diagnose patients at an early age permitting treatment to be initiated prior to the development of heart disease. The ability to identify the molecular defects in patient with elevated blood cholesterol or triglycerides requires in many cases the isolation of mutant plasma proteins for structural studies and for the analysis of the kinetic properties of the mutant protein as compared to the protein isolated from normal subjects. The present studies carried out over the last several years have provided unique opportunities to identify the molecular defect in patient with dyslipoproteinemias. Several different human mutant plasma apolipoproteins have been isolated of which apoA-IIowa and apoE- 4Philadelphia are of particular interest. ApoA-IIowa contained a single amino acid substitution of a glycine->arginine at residue 26. Patients with apoA-IIowa have low levels of plasma HDL, and hereditary systemic amyloidosis with severe renal disease during the late stages of their disease. Kinetic studies have established that the mutant apoA-IIowa is catabolized at a very rapid rate leading to molecular properties of the A-I apolipoprotein leading to the accumulation of the mutant apolipoprotein in tissues. The extracellular accumulation of the mutant A-IIowa apolipoprotein is responsible for the amyloid accumulation in this kindred with hereditary systemic amyloidosis. Studies have also been performed in the kindred with type III hyperlipidemia and apoE- 4Philadelphia which has been shown by DNA sequence analysis to contain two separate mutations, arginine->cysteine at residue 145 and lysine- >glutamic acid at amino acid 13. Kinetic studies have revealed the mutant apoE-4Philadelphia has decreased catabolism and was responsible for the type III hyperlipoproteinemia. Research has also been directed toward the elucidation of the role of apoA-IV in lipoprotein metabolism. A method was developed to isolate apoA-IV from plasma from normal subjects and patients with dyslipoproteinemias. The isolation of apoA-IV has permitted the characterization of the molecular properties of apoA-IV and to determine apolipoprotein A-IV kinetics in normal and hyperlipoproteinemic subjects.